Fulminant Myocarditis with Combination Immune Checkpoint Blockade

Abstract

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.).

Figure 1

Electrocardiographic and immune effects on cardiac muscle following ipilimumab and nivolumab treatment. Patient 1’s ECG rapidly progressed to complete heart block (Panel A) followed by ventricular tachycardia (Panel B). Autopsy demonstrated lymphocytic infiltration in myocardium (intraventricular septum pictured, Panel C). Inflammatory infiltrate was comprised of CD3 positive T lymphocytes (Panel D), many of which were positive for CD8 (Panel E). Only cardiac and skeletal muscle were affected; smooth muscle and other tissue were spared (Panel F). The black arrow denotes esophageal smooth muscle without immune infiltration and the green arrow denotes esophageal skeletal muscle, which is heavily infiltrated by immune cells.

Figure 2

T-cell receptor clones in striated muscle and tumor. T-cell receptor sequencing was performed on cardiac and skeletal muscle, and on pre/post-treatment tumors for each patient (CDR3 region of TCR beta chain, ImmunoSeq, Adaptive Biotechnologies), as previously described^,. T-cell clones prevalence by counts displayed on biaxial plots. Numerous T-cell clones are present in all affected tissues in patient 1 (panel A) and patient 2 (panel B). Red denotes T-cell clones more prevalent in heart tissue and blue denotes more frequent clones in other tissues; for a clonotype to be determined to be differentially present, a P value for each clone in two samples being compared was calculated using a Fisher exact test and adjusted for a positive false discovery rate using the Storey method as described in. Blue arrow denotes that few prevalent T-cell clones were shared between pre-treatment tumor and heart, but numerous shared clones expanded in the post-treatment tumor. Red circle denotes that the highest frequency T-cell clone in the heart was also highly prevalent in skeletal muscle, and expanded from the pre-treatment to post-treatment tumor.